1. Field of the Invention
This invention relates to pharmaceutical compound preparations for oral, percutaneous, intranasal, rectal or parenteral application used in the treatment of hypogonadal men with or without metabolic syndrome and of men with hypophyseal diseases.
2. Prior Art
Various endocrine functions undergo changes in the course of the aging process. The insulin-like growth factor (IGF-1) levels in the plasma diminishes in healthy persons as they get older (Rudman D(1985): Growth hormone, body composition, and aging. J Am Geriatr Soc 33: 800-807; Florini JR, Prinz PN, Vitiello MV, Hintz RL (1985): Somatomedin-C levels in healthy young and old men: Relationship to peak and 34-hour integrated levels of growth hormone. J. Gerontol 40: 2-7). The normal aging process in men is accompanied by a hypofunction of the testicles, in particular, by a decline in serum testosterone levels. At the same time, the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the plasma are increased (Tien-Chun Chang, Chin-Chia Tung, Yung-Lien Hsiao (1994): Hormonal changes in elderly men with non-insulin-dependent diabetes mellitus and the hormonal relationships to abdominal adiposity. Gerontology 40: 260-267).
The prevalence of specific diseases with or without a disturbed oral glucose tolerance increases parallel to these hormonal changes. Examples of this are the various forms of diabetes mellitus, high blood pressure, hypercholesterolaemia and other disorders of the lipid or lipoprotein metabolism, myocardial infarction, and Alzheimer's disease (Vermeulen A (1991): J. Clin Endocrinol Metab 73: 222). Quite frequently, the so-called metabolic syndrome is found in overweight elderly men which is accompanied by obesity, insulin or insulin receptor resistance, a testosterone deficit and a disproportionately high risk of cardiovascular diseases. There is a considerably increased mortality caused by cerebral or coronary ischaemia (McGovern PG et al. (1993): The role of stroke attack rate and case fatality in the decline of stroke mortality. The Minnesota Heart Survey. Ann Epidemiol. 3: 483-487; Hames CG et al. (1993): Black-white comparisons of 20-year coronary heart disease mortality in the Evans County Heart Study Cardiology 82: 122-136).
Patients with serum-testosterone levels that were regularly below 3.5 ng/ml in repeated tests are commonly called hypogonadal, and they are treated with appropriate androgens in a hormone replacement therapy.
Testosterone replacement may be carried out by oral, intramuscular or transdermal (e. g. transscrotal) application. It should be considered here that the testosterone itself may either become effective in specific target tissues by binding to a specific androgen receptor, or by being aromatized into estradiol or reduced to dihydrotestosterone, the effect of the testosterone therefore mainly depending on the extent of aromatization or reduction. Testosterone acts directly at the androgen receptor in specific organs such as the muscles, the skeleton and the testicles. In various peripheral tissues such as the external genitals, accessory sexual glands (e. g. the prostate) and the skin, however, testosterone has first to be reduced to 5.alpha.-dihydrotestosterone to develop its androgenic effect. 5.alpha.-dihydrotestosterone is about twice as active as testosterone. In other tissues such as fatty tissue and certain cerebral areas or cells, testosterone is aromatized into the female sex hormone, estradiol, and acts via the estrogen receptor.
3.0 to 10.0 ng/ml of total testosterone, 2% of which (0.06 to 0.2 ng/ml) present as uncombined, "free" testosterone, 0.25 to 0.75 ng/ml as 5.alpha.-dihydrotestosterone and &lt;50 pg/ml as 17.beta.-estradiol has been measured in the blood of healthy young men (Ikuko Kato et al. (1992): Determinants of sex hormone levels in men as useful indices in hormone-related disorders. J. Clin Epidemiol. 45:1417-1421; Andersson SO et al. (1993): Serum pituitary and sex steroid hormone levels in the ethiology of prostatic cancer-a population-based case-control study. Br. J. Cancer 68: 97-102; Mikuma N et al. (1994): Role of the hypothalamic opioidergic system in the control of gonadotropin secretion in elderly men. Andrologia 26:39-45).
This well-balanced ratio between the parent substance, testosterone, and its two main metabolites, 17.beta.-estradiol and 5.alpha.-dihydrotestosterone is essential for maintaining the physiological equilibrium in males which in turn is responsible for the functioning of the protein, carbohydrate, and lipoprotein metabolisms as well as of the haemopoietic system including fibrinolysis, for the maintenance of the weight of bony and muscular tissue, the functions of the skin and liver, and several behavioural patterns. This illustrates that a disruption to this balance can entail certain states of disease.
Testosterone and estradiol can interact in a very complex way. Estradiol increases the concentration of androgen receptors in certain tissues, thus multiplying the androgenic effect (synergistic effect) while testosterone acts, for example, as an estradiol antagonist in the mammary glands of mice. In addition, androgens in breast cancer cell lines (MCF6 cells) can bind to the estrogen receptor and inhibit the estrogen-dependent progesterone receptor synthesis (antagonistic effect).
The degree to which estrogens are converted and thus the pharmacokinetic profile of the respective androgen can also be influenced by the way in which an androgen molecule is synthetically changed. The orally active 17.alpha.-alkylated androgens can only with difficulty, or not at all, be aromatized to estrogens. They lower the levels of HDL cholesterol, HDL.sub.2 cholesterol and of the apolipo-proteins, AI and AII. They cause an increase in total and LDL cholesterol, apolipoprotein B, hepatic triglyceride lipase, and lipoprotein lipase levels. Unlike the 17.alpha.-alkylated androgens, testosterone esters such as testosterone enanthate only have a minor effect on total and LDL cholesterol levels, though they can cause a minor suppression of HDL cholesterol. This difference between 17.alpha.-alkylated and non-alkylated androgens (e. g. testosterone ester) is due to the capability of testosterone or its esters to be aromatized into estrogens. As is generally known, estrogens act contrary to androgens on LDL and HDL cholesterol levels.
In elderly men, however, the metabolic pattern of testosterone changes considerably, i.e. the balance mentioned above of testosterone, 5.alpha.-dihydrotestosterone and 17.beta.-estradiol is durably disturbed. This modifies the quantitative aspects of testosterone metabolism: more estrogens and less 5.alpha.-reduced metabolites are formed.
Aromatization into estradiol is especially increased in adipose men (De Ligniere B (1993) Transdermal dihydrotestosterone treatment of andropause, Ann Med 25: 235-241). If testosterone or its fatty acid ester is applied to hypogonadal men, a much greater portion is aromatized into estradiol than with healthy men. Estradiol levels in the plasma are increased by 70% after percutaneous application (Kuhn JM Laudat MH, Lignieres de B, Bricaire H. Lutaon JP (1986) Traitement androgenique percutane des hypogonadismes masculins. Efficacite comparee de la testosterone et de la dihydrotestosterone: etude de 40 observations. Contracept Fert Sex 14: 1031-1036). The estradiol levels in the plasma are even doubled after intramuscular injection (Tenover JS (1992) Effects of testosterone supplementation in the aging male. J. Clin Endocrinol Metab 75: 1092-1098). In many patients, this results in estradiol levels similar to those of women during the follicle phase. It is therefore not astonishing that the application of testosterone to hypogonadal, adipose men may cause a series of unwelcome effects such as triggering or intensification of gynaecomastia and a relative peripheral androgen deficit (decrease in libido, reduced size of the genitals, but also prostatic hyperplasia).
The exogenic supply of testosterone, e. g. of testosterone enanthate, to patients in which gonadal testosterone biosynthesis still works soon reversibly inhibits the endogenic testosterone production for a period of about 2 weeks (Humpel M. and Oettel M. (1994): Wertende Zusammenfassung Pharmakokinetik und Biotranformation von Testosteronenanthat beim Menschen). This has not been observed after applying estradiol or dihydrotestosterone (DHT) or mesterolone (Oettel M. (1993) in: Hagers Handbuch der Pharmazeutischen Praxis vols. 7 and 8).
Furthermore, the reductive metabolism to the highly androgenic metabolite, 5.alpha.-dihydrotestosterone, may be disturbed in old age. Much less androgenic metabolites are formed as the 5.beta.-metabolization pattern is intensified rather than the 5.alpha.-metabolic pathway. As a consequence, androgens had to be applied in heavy doses (e. g. 400 to 600 mg testosterone undecanoate/day orally or 200 to 250 mg testosterone enanthate i. m. every 2 to 3 weeks) to achieve the desired androgenic effects. This inevitably increases estradiol levels with the unwelcome side effects mentioned above.
According to Yarnell JWG et al. 1993 (Arterioscl. Thromb. 13: 517-520), estradiol levels in the blood plasma are slightly increased in men with a severe ischaemic heart disease. This Caerphilly Prospective Study involved a total of 2161 healthy control persons aged from 45 to 59 years with estradiol levels in the plasma at 69+/-17 pg/ml (250+/-61 pmol/l), and 134 men of similar age suffering from severe ischaemic heart disease with levels at 71+/-19 pg/ml (257+/-69 pmol/l).
The advantages of estradiol at a low concentration are indispensable, though (as is the case when administering non-aromatizable dihydrotestosterone or one of its derivatives). These advantages include an improvement of cognitive performance, an increase in the level of sex hormone-binding globulin (SHBG), the inhibition of LDL cholesterol oxidation as an important step in atherogenesis, arterial dilatation and the associated improved blood flow through the tissue, and the inhibition of increased gonadotropin and inhibin levels (Harman SM. Blackman MR. (1994) Male menopause, myth or menace? Endocrinologist 4:212-217). Moreover, estradiol seems to prevent age-dependent transformation processes in proteohormones (Wide L. Maessen T. (1994) 17.beta.-Estradiol counteracts the formation of the more acidic isoforms of follicle-stimulating hormone and luteinizing hormone after menopause. Clin Endocronol 40: 783-789).
The efficiency of the unchanged testosterone is also clearly reduced in old age as the most important transport protein, sex hormone-binding globulin (SHBG) binds testosterone much stronger through structural transformation processes. As a result, the portion of free, i.e. biologically active testosterone becomes smaller. 5.alpha.-Dihydrotestosterone and estradiol, unlike unchanged testosterone, do not show a significant decrease in old age (Vermeulen A. (1972) Testosterone secretion and metabolism in male senescence. J Clin Endocrinol 34: 730-735).
It is the object of the present invention to provide appropriate pharmaceutical formulations that can prevent the imbalances of testosterone metabolism in old age, in cases of hypophyseal diseases, hypogonadism and/or metabolic syndrome, thereby maintaining the balance of androgens and estradiol known from healthy young men in male senescence as well.